rs781734224
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PP3_ModerateBS2_Supporting
The NM_213599.3(ANO5):āc.749A>Gā(p.Tyr250Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000168 in 1,610,208 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā ā ).
Frequency
Genomes: š 0.000046 ( 0 hom., cov: 32)
Exomes š: 0.000014 ( 0 hom. )
Consequence
ANO5
NM_213599.3 missense
NM_213599.3 missense
Scores
8
9
2
Clinical Significance
Conservation
PhyloP100: 2.91
Genes affected
ANO5 (HGNC:27337): (anoctamin 5) This gene encodes a member of the anoctamin family of transmembrane proteins. The encoded protein is likely a calcium activated chloride channel. Mutations in this gene have been associated with gnathodiaphyseal dysplasia. Alternatively spliced transcript variants have been described. [provided by RefSeq, Nov 2009]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 1 ACMG points.
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.903
BS2
?
High AC in GnomAd4 at 7 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ANO5 | NM_213599.3 | c.749A>G | p.Tyr250Cys | missense_variant | 8/22 | ENST00000324559.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ANO5 | ENST00000324559.9 | c.749A>G | p.Tyr250Cys | missense_variant | 8/22 | 1 | NM_213599.3 | P2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000460 AC: 7AN: 152128Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000239 AC: 6AN: 250906Hom.: 0 AF XY: 0.0000295 AC XY: 4AN XY: 135598
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GnomAD4 exome AF: 0.0000137 AC: 20AN: 1458080Hom.: 0 Cov.: 30 AF XY: 0.0000152 AC XY: 11AN XY: 725586
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GnomAD4 genome ? AF: 0.0000460 AC: 7AN: 152128Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3AN XY: 74306
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Aug 15, 2016 | - - |
Gnathodiaphyseal dysplasia;C1969785:Autosomal recessive limb-girdle muscular dystrophy type 2L Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 02, 2024 | This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 250 of the ANO5 protein (p.Tyr250Cys). This variant is present in population databases (rs781734224, gnomAD 0.01%). This missense change has been observed in individual(s) with clinical features of ANO5-related conditions (PMID: 32528171; Invitae). ClinVar contains an entry for this variant (Variation ID: 286191). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ANO5 protein function with a positive predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Autosomal recessive limb-girdle muscular dystrophy type 2L Uncertain:1
Uncertain significance, criteria provided, single submitter | research | Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard | - | The heterozygous p.Tyr250Cys variant was identified in the compound heterozygous state by our study in one individual with Limb-Girdle Muscular Dystrophy. The p.Tyr250Cys variant has been reported as a VUS in 2 individuals in ClinVar (ID: 286191). It has also been identified in 0.01% (1/10378) of African chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org). The Tyrosine (Tyr) at position 250 is not conserved in mammals or evolutionary distant species, raising the possibility/supporting that a change at this position may be tolerated. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the p.Tyr250Cys variant is uncertain. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
CADD
Benign
DANN
Uncertain
DEOGEN2
Uncertain
T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Pathogenic
D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D
MetaSVM
Uncertain
D
MutationAssessor
Pathogenic
M
MutationTaster
Benign
D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D
REVEL
Pathogenic
Sift
Pathogenic
D
Sift4G
Pathogenic
D
Polyphen
D
Vest4
MutPred
Loss of phosphorylation at Y250 (P = 0.0513);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at